1. Field of the Invention
This invention relates to a dialytic solution for peritoneal dialysis. More particularly, this invention relates to a dialytic solution for peritoneal dialysis, which is free from the danger latent in the load exerted on the patient by an osmotic pressure regulating agent contained in the dialytic solution.
2. Description of the Prior Art
As one method for the treatment of patients suffering from renal failure or from intoxication with poisons or violent substances, the dialytic therapy has been in application for a long time. Broadly, this dialytic therapy is divided into hemodialysis and peritoneal dialysis. The hemodialysis is effected by drawing the patient's blood out of his body, introducing the blood into an artificial kidney, i.e. a dialyzer provided with an artificial dialytic membrane, allowing metabolic wastes contained in the blood to diffuse through the artificial membrane and pass into a washing perfusing solution, and removing excess water through ultrafiltration utilizing the pressure adjusted with an external circulating device. The peritoneal dialysis is effected by directly injecting a dialytic solution into the patient's abdominal cavity, allowing the metabolic wastes contained in the blood to diffuse through the peritoneum and pass into the dialytic solution, and removing excess water by virtue of the difference in the osmotic pressure produced between the injected hypertonic dialytic solution and the body fluid.
For the dialytic therapy, the hemodialysis has chiefly found application to date because the peritoneal dialysis is liable to induce peritonitis. The peritoneal dialysis has been selectively adopted for cases of blood access trouble, complications, and senility for which the hemodialysis is not suitable. The hemodialysis has been demonstrated to permit elongation of the patient's life by not less than 20 years on the condition that it is applied smoothly. Further the fact that most patients under sustained treatment of hemodialyisis visit hospitals regularly for the treatment apparently indicates that this therapy contributes appreciably to the patient's return to normal social life. The hemodialysis in current use, however, does not prove fully satisfactory. For example, it does not infrequently, induce such uncontrollable complications as insufficient immunity, anemia, nutritional disorder, bone trouble, dysarteritony, and vascular sclerosis. Further, the patients find their regular visits to hospitals for protracted periodic treatments troublesome. Moreover, part of the diseases induced by the therapy of hemodialysis are treated by existing methods intermittently at the rate of two or three times a week. These diseases are undeniably ascribable to the fact that the dialytic membranes and the dialytic solutions currently in use are deficient in vital adaptability.
Recently, the continuous ambulatory peritoneal dialysis (CAPD) has been established as one form of the peritoneal dialysis. This CAPD is rapidly disseminating as one method of dialytic therapy. This is because the CAPD which comprises keeping a dialytic solution retained at all times within the abdominal cavity, repeating discharge and injection of the dialytic solution at intervals of 4 to 8 hours, and thus using 4 to 10 liters of the dialytic solution daily provides eficient dialysis, because the dialysis constitutes itself a sustained treatment, because the dialysis exerts no heavy physiological load upon the patient, because the peritoneum excels the artificial dialytic membrane in the removal of medium to high molecular weight solutes and, therefore, the problem of vital adaptability inherent in the artificial membrane is not encountered, because the dialytic solution to be used can be of a far more refined grade, because the dialysis has no use for any large apparatus and is relatively simple to operate and, therefore, suits home treatment, because the patient is allowed to decrease the frequency of hospital visit and enjoys a reduction in the expense of treatment, and because burden of dietary restriction is lessened. Besides these advantages which the hemodialysis fails to offer, the CAPD promises elimination of part of the disease inherently induced by the hemodialysis and further factilitates the patient's return to normal social life.
There are indications that the peritoneal dialysis centering on the CAPD will occupy an increasingly important position as one method for the purification of blood in the future.
The dialytic solutions used for the peritoneal dialysis are varied in minute details by the difference in the manner of peritoneal dialysis as between the CAPD and the intermittent peritoneal dialysis (IPD). Basically, however, they are similar in respect that they invariably comprise electrolytes represented by Na.sup.+ ion, Ca.sup.2+ ion, Mg.sup.2+ ion, and Cl.sup.- ion, alkalinizing agents typified by lactate and acetate, and osmotic pressure regulating agents. In Table 1, the basic compositions of the peritoneal dialytic solutions currently in general use or in clinical use are shown in comparison with the composition of blood plasma.
TABLE 1 __________________________________________________________________________ Basic composition of dialytic solution for peritoneal dialysis (theoretical) Osmotic Na Ca Mg Cl Lactate Glucose pressure Name pH (mEq/l.) (mEq/l.) (mEq/l.) (mEq/l.) (mEq/l.) (mg/dl) (mOsm/l.) __________________________________________________________________________ Perisorita*.sup.1 140 4.5 1.5 101 45 1300 361.2 Perisorita (G)*.sup.1 140 4.5 1.5 101 45 7000 677.9 Perisorita Na 130*.sup.1 130 4.5 1.5 98 38 1600 357.9 Perisorita Na 130 (G)*.sup.1 130 4.5 1.5 98 38 7000 657.9 EL Reflac No. 1*.sup.2 140 4.0 1.5 102 43 1500 371.0 EL Reflac No. 2*.sup.2 140 4.0 1.5 102 43 7000 676.6 CAPD-135*.sup.3 5.5 135 4.0 1.5 105.5 35 1350 355 CAPD-250*.sup.3 5.5 135 4.0 1.5 105.5 35 2500 419 CAPD-400*.sup.3 5.5 135 4.0 1.5 105.5 35 4000 500 Plasma 7.4 140 5.0 1.5 100 100 280 __________________________________________________________________________ *.sup.1 Shimizu Pharmaceutical *.sup.2 Morishita Pharmaceutical *.sup.3 Terumo K. K.
In the peritoneal dialysis as described above, since the difference in osmotic pressure between the body fluid and the dialytic solution is utilized for the removal of excess water contained in the body fluid, the osmotic pressure of the dialytic solution for the peritoneal dialysis must be maintained at a higher level than that of the patient's blood plasma. Thus, the dialytic solution for the peritoneal dialysis is required to incorporate therein an osmotic pressure regulating agent, i.e. a solute for hightening the osmotic pressure thereof. Generally, as the osmotic pressure regulating agent, glucose is used as mentioned above. The solute which is contained as the osmotic pressure regulating agent in the dialytic solution for the peritoneal dialysis is diffused through the peritoneum into the body fluid by entirely the same mechanism as the metabolic wastes contained in the body fluid, specifically such electrolytes as Na.sup.+ ion and Cl.sup.- ion and such solutes as urea and creatinine are diffused through the peritoneum into the dialytic solution for the peritoneal dialysis. In fact, the glucose content of the electrolytic solution decreases with the lapse of time when the electrolytic solution is actually used for the peritoneal dialysis. When the glucose is used as the osmotic pressure regulating agent in the dialytic solution for the peritoneal dialysis as described above, therefore, the peritoneal dialysis causes sustained absorption of the glucose into the patient's body. This forced assimilation of the high-calorie sugar by the peritoneal dialysis has the latent danger of exposing the patient to aggravation of corpulence, arteriosclerosis, compelling the patient of diabetes to strive for maintenance of blood sugar content, and inducing accelerated complication of various diseases.
Various studies are now under way for the purpose of overcoming the disadvantages caused by the glucose contained in the dialytic solutions currently in common use for the peritoneal dialysis. For example, use of glycerol as an osmotic pressure regulating agent in the place of glucose has been proposed [S. Yuasa et al: "Clinical evaluation of peritoneal dialysis with glycerol dialysate," Toseki Kaishi, 14, 279-284, 1981 (5); D. E. Ralph et al.: "Dialysis soln.contg. glycerol and opt. amino acid source, esp. for ambulatory peritoneal dialysis,"; U.S. Patent Ser. No. 263,818 (corresponding to Japanese Patent Application SHO No. 56(1981)-187,674), B. Lindholm et al.: "Glycerol as osmotic agent in perinoteal dialysis (PD)"; Artificial Organs, 7A, 47, 1983 (Nov.)]. Since glycerol has a small molecular weight, specifically about one half of the molecular weight of glucose, it permits required adjustment of the osmotic pressure at a low application rate and lessens the caloric burden on the patient. Glycerol has no use for insulin in completing its main path of metabolism and undergoes metabolism quickly and completely. It has only a sparing possibility of increasing the blood sugar level. Thus, glycerol enjoys various advantages not found in glucose. Lindholm et al. pointed out in their report that since glycerol has a small molecular weight as compared with glucose and diffuses quickly through the peritoneum in the patient's body, the osmotic pressure required for the removal of excess water during the sustained retention of the dialytic solution within the abdominal cavity cannot be maintained for a long time. We, in our qualitative animal (rat) test using glucose and glycerol, have confirmed the same trend as Lindholm et al. It has been known for a long time that animals, when parenterally given large doses of glycerol, discharge hemoglobinuria. It is generally held that the manifestation of hemoglobin is ascribed to the red blood-corpuscles in the blood [V. Johnson, A. J. Carlson, and A. Johnson: "Am. J. Physiol.," 103, 517, 1933; G. R. Cameron and E. S. Fingkh: "J. Path. Bact.," 51, 165, 1956; A. J. Spiegel and M. M. Noseworthy: "J. Pharm. Sci.," 52, 917, 1963]. The hemolytic action of glycerol is interpreted as a phenomenon that the glycerol causes part of the lipid of the erythrocytic membrane to be dissolved out into the solute and includes dehydration of the erythrocytic membrane [Masayuki Arakawa: "Hemolytic action of glycerol and antihemolytic action of fructose," Journal of Japan Pharmacology Society, 73, 541-547, 1977]. We have conducted an animal (rat) test on the intra-abdominal administration of highly concentrated glycerol solution based on the prior knowledge mentioned above to find that in the group of rats given a dose of 10 g/dl of glycerol, conspicuous hemolysis is recognized in 10 minutes after the administration when the glycerol concentration in the serum is 163 mg/dl. It has been further observed that this degree of hemolysis varies with the lapse of time, reaching its peak 60 minutes after the administration when the glycerol concentration in the serum is 250 mg/dl and persisting until 180 minutes after the administration when the glycerol concentration in the serum is 181 mg/dl. In an additional test, it has been learned that similar results are obtained in the group of rats intra-abdominally given glycerol in such doses that the glycerol concentrations in the serum exceed the level of 150 to 200 mg/dl. These results of the additional test conducted by the inventors suggest that the hemolytic action of glycerol is possibly produced not only by the direct injection into the blood such as the intravenous injection but also by the intra-abdominal administration. It is said that the hemolytic action of glycerol is heavily affected by the difference in species and the human red-blood corpuscles are relatively less susceptible to the hemolytic action. In the light of the mechanism of the hemolysis to be reasonably assumed, the latent danger involved when a dialytic solution containing glycerol as an osmotic pressure regulating agent which is used a long time for peritoneal dialysis cannot be ignored.
This invention, therefore, aims to solve the problem mentioned above.
To be specific, an object of this invention is to provide an improved dialytic solution for peritoneal dialysis.
Another object of this invention is to provide a dialytic solution for peritoneal dialysis, which has no latent danger in the load exerted upon the patient by an osmotic pressure regulating agent contained in the dialytic solution for peritoneal dialysis.
A further object of this invention is to provide a dialytic solution for peritoneal dialysis, which permits highly safe protracted use and proves particularly advantageous for the purpose of CAPD.